Prolonged seizure activity, as occurs during status epilepticus(SE), is neuropathologically characterized by aberrant cell death in vulnerable neuronal populations. It is believed that this neuronal loss not only underlies the neurological deficits clinically characterizing SE but may also contributeto the neuronal reorganization occurring in the aftermath of SE. Substantial evidence indicates that seizure activity has a dual influence on cellular damage and repair, the balance of which depends on the severity and duration of seizure activity. Elucidating the seizure-induced regulation of endogenous neuronal repair systems may provide insights into processes that contribute to chronic epileptic conditions. Moreover, it may clarify determinants of cellular vulnerability to programmed cell death (PCD). I propose the working hypothesis that the regulation of one of these defense mechanisms, DNA double-strandbreak (DSB) repair, is altered by seizure activity, and that the direction of this alteration depends upon seizure severity. To investigate this hypothesis, I will evaluate the spatio-temporal profile of regulation of DNA DSB repair protein expression levels and activity following different severities of SE. Moreover, I will evaluate how both injurious and noninjurious neuroprotective seizure preconditioning influences the regulation of DNA DSB repair. These studies will help to elucidate the short- and long-term neuronal changes that occur during and in the aftermath of SE. Moreover, they will provide insights into novel neuroprotective mechanisms.